DESCRIPTION (applicant's abstract): Our long term goal is to understand the mechanism by which a line of communication is maintained between the immune system and the sympathetic nervous system, as well as the mechanism by which disruption of this communication link affects immune homeostasis. Sympathetic nerve fibers release norepinephrine within lymphoid organs during an immune response to bind to adrenergic receptors expressed on immune cells. Findings from this laboratory show that B cells and clones of CD4+ T-helper (Th)-1 cells express detectable levels of the beta-2-adrenergic receptor (b2AR) protein and mRNA, while clones of Th2 cells do not. Our results also show that b2AR stimulation on the B cell, but not the Th2 cell, increases the frequency of B cells that differentiate into IgM-, IgG1-, and IgE-secreting cells through a mechanism that appears to involve a b2AR-induced increase in B7-2 expression on the B cell. In contrast, b2AR stimulation on the Th1 cell appears to play a more critical role to increase the frequency of B cells that differentiate into IgG2a-secreting cells. However, in both the Th1 and Th2 cell-dependent antibody response, enhancement appears to depend on the activation state of the cells at the time of b2AR stimulation. These findings have led us to propose the hypothesis that norepinephrine stimulation of the b2AR on lymphocytes is essential for the induction of maximal antibody production against a Th cell-dependent antigen. The specific aims of this research will be 1) To determine if the presence of the b2AR on lymphocytes is essential for norepinephrine to enhance the antibody response by using mice in which the b2AR gene has been disrupted; 2) To determine the mechanism responsible for antibody enhancement by testing if the increase in B cell activity is induced directly by b2AR stimulation on the B cell and/or induced indirectly by the B cell influencing Th cell activity and/or by b2AR stimulation on the Th1 cell; and 3) To determine the mechanism by which the antibody enhancement is influenced by the time of b2AR stimulation in relation to the state of Th cell and B cell activation. For all experiments, cells from b2AR knockout mice will be used to confirm findings obtained from cells of normal mice. These studies will provide not only insight into the mechanisms important to homeostatic regulation by norepinephrine of the Th cell-dependent antibody response, but also insight into the rational development of approaches by which changes in antibody production associated with immune and nervous system diseases can be prevented and reversed.